Bipolar affective disorder (BP) is heavily influenced by genetic factors. Linkage studies using molecular genetic methods have been successful in localizing genes for many disorders in recent years, including one form of manic depressive illness on chromosome 11. Another recent report using traditional linkage methods traced manic depressive illness to the X chromosome in a separate group of families. This and additional data suggest heterogeneity in this condition, although neither finding has been independently replicated at this time. A cooperative study is proposed to ascertain additional families informative for linkage. The state of Indiana will be an excellent resource for identification and assessment of large pedigrees with these illnesses. Families, especially in the rural areas of the state, tend to be stable. There is an organized state mental health system with a tradition of referral to the Medical Center in Indianapolis. Probands with bipolar illness will be systematically ascertained at the 9 facilities affiliated with Indiana University Medical Center. Promising families will have direct interviews of first-degree relatives and more distant relatives if additional cases of illness are confirmed. We will be seeking families with a minimum of four or more affectively ill persons including 2 BP siblings. We have identified 20 such Families thus far and expect to have 70-80 at the end of the grant period. Families satisfying criteria will have blood taken for DNA extraction and for transformation into lymphoblast lines for storage and culture. Probands and ill relatives will be systematically evaluated for biologic studies. Those suitable will be tested by assessing melatonin response to light. In addition blood samples will be stored for future marker determination.